Platelets play an important role in the initiation and propagation of atherosclerosis and, more so, in the ensuing atherothrombotic complications. Although the standard antiplatelet drugs reduce the risk of atherothrombotic complications in high-risk patients, they are not very effective in diabetes mellitus (DM) subjects. The reasons for this remains unclear but likely due to increased production/release of reticulated platelets (RP) from the bone marrow (BM). The RPs are immature, larger in size, hyperreactive, and less responsive to standard anti- platelet drugs. Platelet production is tightly regulated by the hormone thrombopoietin (TPO) and its receptor, c- MPL, which is found on several BM progenitor cells. While TPO is constitutively produced from BM stromal cells and the kidney, the liver becomes their major source during inflammation where hepatic TPO production is increased through the actions of interleukin-6 (IL-6). Our preliminary data suggests that hyperglycemia enhances platelet biogenesis via mechanisms that involve neutrophil-derived S100A8/A9, a Damage Associated Molecular Pattern (DAMP) complex, Kupffer cell (KC)-derived interleukin-6 (IL-6), and hepatic TPO. Studies in humans have also found a positive correlation between plasma S100A8/A9, IL-6, and platelet aggregation. Most importantly increased serum S100A8/A9 is associated with reduced anti-platelet effects of aspirin. Based on our preliminary data and the clinical evidence, we hypothesize that hyperglycemia-induced IL-6 production from hepatic KCs elevates plasma TPO and initiate thrombocytopoiesis resulting in higher proportion of RPs in the blood. The newly formed RPs, being hyperreactive, enhance platelet-leukocyte interactions and contribute to atherothrombotic complications. In order to test this hypothesis, firstly, we will examine how glucose enhances the production of RPs in diabetes. We will specifically identify the cross talk between circulating neutrophils and KCs by manipulating blood glucose, neutrophils, serum S100A8/A9 and RAGE/IL6 signaling in KCs and study how these manipulations affect RP production. Secondly, we will assess the atherogenic and thrombogenic properties of RPs in diabetes by performing various platelet function assays both in mice and type 2 DM subjects. The findings from these studies will have a broader impact on the current anti-platelet therapy particularly in DM subjects as there is a great potential for discovery of novel targets to treat cardiovascular disease.